Phase i trials using sleeping beauty to generate CD19-specific CAR T cells

Partow Kebriaei, Harjeet Singh, M. Helen Huls, Matthew J. Figliola, Roland Bassett, Simon Olivares, Bipulendu Jena, Margaret J. Dawson, Pappanaicken R. Kumaresan, Shihuang Su, Sourindra Maiti, Jianliang Dai, Branden Moriarity, Marie Andrée Forget, Vladimir Senyukov, Aaron Orozco, Tingting Liu, Jessica McCarty, Rineka N. Jackson, Judy S. Moyes & 19 others Gabriela Rondon, Muzaffar Qazilbash, Stefan Ciurea, Amin Alousi, Yago Nieto, Katy Rezvani, David Marin, Uday Popat, Chitra Hosing, Elizabeth J. Shpall, Hagop Kantarjian, Michael Keating, William Wierda, Kim Anh Do, David A. Largaespada, Dean A. Lee, Perry B. Hackett, Richard E. Champlin, Laurence J N Cooper

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

BACKGROUND. T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR. METHODS. T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines. Twenty-six patients with advanced non-Hodgkin lymphoma and acute lymphoblastic leukemia safely underwent hematopoietic stem cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n = 7) or allogeneic settings (n = 19). RESULTS. SB-mediated genetic transposition and stimulation resulted in 2,200- to 2,500-fold ex vivo expansion of genetically modified T cells, with 84% CAR expression, and without integration hotspots. Following autologous HSCT, the 30-month progression-free and overall survivals were 83% and 100%, respectively. After allogeneic HSCT, the respective 12-month rates were 53% and 63%. No acute or late toxicities and no exacerbation of graft-versus-host disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients. CONCLUSIONS. CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT. These results support further clinical development of this nonviral gene therapy approach.

Original languageEnglish (US)
Pages (from-to)3363-3376
Number of pages14
JournalJournal of Clinical Investigation
Volume126
Issue number9
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

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Beauty
Hematopoietic Stem Cell Transplantation
T-Lymphocytes
Antigen Receptors
T-Cell Antigen Receptor
Cytokines
Transposases
Antigens
Graft vs Host Disease
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Genetic Therapy
Non-Hodgkin's Lymphoma
Disease-Free Survival
Neoplasms
Plasmids
B-Lymphocytes
CD19-specific chimeric antigen receptor
DNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kebriaei, P., Singh, H., Huls, M. H., Figliola, M. J., Bassett, R., Olivares, S., ... Cooper, L. J. N. (2016). Phase i trials using sleeping beauty to generate CD19-specific CAR T cells. Journal of Clinical Investigation, 126(9), 3363-3376. https://doi.org/10.1172/JCI86721

Phase i trials using sleeping beauty to generate CD19-specific CAR T cells. / Kebriaei, Partow; Singh, Harjeet; Huls, M. Helen; Figliola, Matthew J.; Bassett, Roland; Olivares, Simon; Jena, Bipulendu; Dawson, Margaret J.; Kumaresan, Pappanaicken R.; Su, Shihuang; Maiti, Sourindra; Dai, Jianliang; Moriarity, Branden; Forget, Marie Andrée; Senyukov, Vladimir; Orozco, Aaron; Liu, Tingting; McCarty, Jessica; Jackson, Rineka N.; Moyes, Judy S.; Rondon, Gabriela; Qazilbash, Muzaffar; Ciurea, Stefan; Alousi, Amin; Nieto, Yago; Rezvani, Katy; Marin, David; Popat, Uday; Hosing, Chitra; Shpall, Elizabeth J.; Kantarjian, Hagop; Keating, Michael; Wierda, William; Do, Kim Anh; Largaespada, David A.; Lee, Dean A.; Hackett, Perry B.; Champlin, Richard E.; Cooper, Laurence J N.

In: Journal of Clinical Investigation, Vol. 126, No. 9, 01.09.2016, p. 3363-3376.

Research output: Contribution to journalArticle

Kebriaei, P, Singh, H, Huls, MH, Figliola, MJ, Bassett, R, Olivares, S, Jena, B, Dawson, MJ, Kumaresan, PR, Su, S, Maiti, S, Dai, J, Moriarity, B, Forget, MA, Senyukov, V, Orozco, A, Liu, T, McCarty, J, Jackson, RN, Moyes, JS, Rondon, G, Qazilbash, M, Ciurea, S, Alousi, A, Nieto, Y, Rezvani, K, Marin, D, Popat, U, Hosing, C, Shpall, EJ, Kantarjian, H, Keating, M, Wierda, W, Do, KA, Largaespada, DA, Lee, DA, Hackett, PB, Champlin, RE & Cooper, LJN 2016, 'Phase i trials using sleeping beauty to generate CD19-specific CAR T cells', Journal of Clinical Investigation, vol. 126, no. 9, pp. 3363-3376. https://doi.org/10.1172/JCI86721
Kebriaei P, Singh H, Huls MH, Figliola MJ, Bassett R, Olivares S et al. Phase i trials using sleeping beauty to generate CD19-specific CAR T cells. Journal of Clinical Investigation. 2016 Sep 1;126(9):3363-3376. https://doi.org/10.1172/JCI86721
Kebriaei, Partow ; Singh, Harjeet ; Huls, M. Helen ; Figliola, Matthew J. ; Bassett, Roland ; Olivares, Simon ; Jena, Bipulendu ; Dawson, Margaret J. ; Kumaresan, Pappanaicken R. ; Su, Shihuang ; Maiti, Sourindra ; Dai, Jianliang ; Moriarity, Branden ; Forget, Marie Andrée ; Senyukov, Vladimir ; Orozco, Aaron ; Liu, Tingting ; McCarty, Jessica ; Jackson, Rineka N. ; Moyes, Judy S. ; Rondon, Gabriela ; Qazilbash, Muzaffar ; Ciurea, Stefan ; Alousi, Amin ; Nieto, Yago ; Rezvani, Katy ; Marin, David ; Popat, Uday ; Hosing, Chitra ; Shpall, Elizabeth J. ; Kantarjian, Hagop ; Keating, Michael ; Wierda, William ; Do, Kim Anh ; Largaespada, David A. ; Lee, Dean A. ; Hackett, Perry B. ; Champlin, Richard E. ; Cooper, Laurence J N. / Phase i trials using sleeping beauty to generate CD19-specific CAR T cells. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 9. pp. 3363-3376.
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abstract = "BACKGROUND. T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR. METHODS. T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines. Twenty-six patients with advanced non-Hodgkin lymphoma and acute lymphoblastic leukemia safely underwent hematopoietic stem cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n = 7) or allogeneic settings (n = 19). RESULTS. SB-mediated genetic transposition and stimulation resulted in 2,200- to 2,500-fold ex vivo expansion of genetically modified T cells, with 84{\%} CAR expression, and without integration hotspots. Following autologous HSCT, the 30-month progression-free and overall survivals were 83{\%} and 100{\%}, respectively. After allogeneic HSCT, the respective 12-month rates were 53{\%} and 63{\%}. No acute or late toxicities and no exacerbation of graft-versus-host disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients. CONCLUSIONS. CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT. These results support further clinical development of this nonviral gene therapy approach.",
author = "Partow Kebriaei and Harjeet Singh and Huls, {M. Helen} and Figliola, {Matthew J.} and Roland Bassett and Simon Olivares and Bipulendu Jena and Dawson, {Margaret J.} and Kumaresan, {Pappanaicken R.} and Shihuang Su and Sourindra Maiti and Jianliang Dai and Branden Moriarity and Forget, {Marie Andr{\'e}e} and Vladimir Senyukov and Aaron Orozco and Tingting Liu and Jessica McCarty and Jackson, {Rineka N.} and Moyes, {Judy S.} and Gabriela Rondon and Muzaffar Qazilbash and Stefan Ciurea and Amin Alousi and Yago Nieto and Katy Rezvani and David Marin and Uday Popat and Chitra Hosing and Shpall, {Elizabeth J.} and Hagop Kantarjian and Michael Keating and William Wierda and Do, {Kim Anh} and Largaespada, {David A.} and Lee, {Dean A.} and Hackett, {Perry B.} and Champlin, {Richard E.} and Cooper, {Laurence J N}",
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T1 - Phase i trials using sleeping beauty to generate CD19-specific CAR T cells

AU - Kebriaei, Partow

AU - Singh, Harjeet

AU - Huls, M. Helen

AU - Figliola, Matthew J.

AU - Bassett, Roland

AU - Olivares, Simon

AU - Jena, Bipulendu

AU - Dawson, Margaret J.

AU - Kumaresan, Pappanaicken R.

AU - Su, Shihuang

AU - Maiti, Sourindra

AU - Dai, Jianliang

AU - Moriarity, Branden

AU - Forget, Marie Andrée

AU - Senyukov, Vladimir

AU - Orozco, Aaron

AU - Liu, Tingting

AU - McCarty, Jessica

AU - Jackson, Rineka N.

AU - Moyes, Judy S.

AU - Rondon, Gabriela

AU - Qazilbash, Muzaffar

AU - Ciurea, Stefan

AU - Alousi, Amin

AU - Nieto, Yago

AU - Rezvani, Katy

AU - Marin, David

AU - Popat, Uday

AU - Hosing, Chitra

AU - Shpall, Elizabeth J.

AU - Kantarjian, Hagop

AU - Keating, Michael

AU - Wierda, William

AU - Do, Kim Anh

AU - Largaespada, David A.

AU - Lee, Dean A.

AU - Hackett, Perry B.

AU - Champlin, Richard E.

AU - Cooper, Laurence J N

PY - 2016/9/1

Y1 - 2016/9/1

N2 - BACKGROUND. T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR. METHODS. T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines. Twenty-six patients with advanced non-Hodgkin lymphoma and acute lymphoblastic leukemia safely underwent hematopoietic stem cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n = 7) or allogeneic settings (n = 19). RESULTS. SB-mediated genetic transposition and stimulation resulted in 2,200- to 2,500-fold ex vivo expansion of genetically modified T cells, with 84% CAR expression, and without integration hotspots. Following autologous HSCT, the 30-month progression-free and overall survivals were 83% and 100%, respectively. After allogeneic HSCT, the respective 12-month rates were 53% and 63%. No acute or late toxicities and no exacerbation of graft-versus-host disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients. CONCLUSIONS. CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT. These results support further clinical development of this nonviral gene therapy approach.

AB - BACKGROUND. T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR. METHODS. T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines. Twenty-six patients with advanced non-Hodgkin lymphoma and acute lymphoblastic leukemia safely underwent hematopoietic stem cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n = 7) or allogeneic settings (n = 19). RESULTS. SB-mediated genetic transposition and stimulation resulted in 2,200- to 2,500-fold ex vivo expansion of genetically modified T cells, with 84% CAR expression, and without integration hotspots. Following autologous HSCT, the 30-month progression-free and overall survivals were 83% and 100%, respectively. After allogeneic HSCT, the respective 12-month rates were 53% and 63%. No acute or late toxicities and no exacerbation of graft-versus-host disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients. CONCLUSIONS. CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT. These results support further clinical development of this nonviral gene therapy approach.

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U2 - 10.1172/JCI86721

DO - 10.1172/JCI86721

M3 - Article

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SN - 0021-9738

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